Synthesis and SAR of highly selective MMP-13 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.08.001

The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13 inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are described.

Full text of DOI:10.1016/j.bmcl.2005.08.001

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4961–4966
Synthesis and SAR of highly selective MMP-13 inhibitors
Jianchang Li,a,* Thomas S. Rush, III,a Wei Li,a Dianne DeVincentis,a
Xuemei Du,c Yonghan Hu,a Jennifer R. Thomason,a Jason S. Xiang,a
Jerauld S. Skotnicki,c Steve Tam,a Kristina M. Cunningham,a
Priya S. Chockalingam,b Elisabeth A. Morrisb and Jeremy I. Levinc
aDepartment of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA
bDepartment of WomenÕs Health and Bone, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA
cDepartment of Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA
Received 18 April 2005; revised 3 August 2005; accepted 4 August 2005
Available online 8 September 2005
Abstract—The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13
inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are
described.
Ó 2005 Elsevier Ltd. All rights reserved.
MMP-13 (matrix metalloproteinase-13, also known as
collagenase-3) belongs to a large family of zinc-contain-
ing enzymes that are involved in the degradation
and remodeling of extracellular matrix proteins. The
expression of MMP-13 by chondrocytes in human
osteoarthritic cartilage and its activity against type II
collagen, the main structural component of articular
cartilage, suggest that this enzyme plays a crucial role
in the etiology of osteoarthritis,1 and that inhibition of
MMP-13 may provide an effective treatment paradigm
for this disease. The therapeutic potential for potent,
orally active, small molecule inhibitors of MMP-13,
and other MMPs, to treat a variety of pathologies
including arthritis, cancer, and pulmonary disease, has
made them prime targets for drug development.2
We have recently disclosed10 compound 1 (Fig. 1)
(R1 = R2 = R3 = H), an early lead compound in our
MMP-13 program, which shows excellent selectivity
for MMP-13 over MMP-1, MMP-9, MMP-14, Aggre-
canase 1 (Agg1), and TACE due to its long, rigid P10
group. However, compound 1 lacks selectivity against
some other MMPs, including MMP-2, MMP-3, MMP-
7, and MMP-8.
In an effort to improve the selectivity of 1, available
MMP X-ray data were examined and computer model-
ing analyses of MMP S10 subsites were performed.
These studies indicated that the loop region of MMP-2
that forms its S10 pocket is two amino acids shorter than
the analogous region in MMP-13. Thus, the S10 pocket
of MMP-2 is constricted, relative to that of MMP-13.
Structure-based design indicated that incorporating a
substituent at the 4-position (R2) of the benzofuran
would take advantage of this size difference and enhance
selectivity. This structural analysis also indicated that if
Early preclinical testing of non-selective MMP inhibi-
tors has shown that these inhibitors are able to prevent
the destruction of cartilage in some animal models of
osteoarthritis.3 However, clinical trials of broad spec-
trum MMP inhibitors have also been plagued by dose-
limiting toxicity in the form of musculoskeletal side
effects.4 This side effect has been postulated to result
from the inhibition of MMP-1, or MMP-14, or sheddas-
es, such as TACE. As a result, interest in more selective
MMP-13 inhibitors has increased.5–9
R2
4
R1
O
OO S
NH
R3
3
NH
O
5
HO
O
(1)
*
Figure 1. Benzofuran amide biphenyl sulfonamide carboxylates.
Corresponding author. E-mail: JCLI@wyeth.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.001

4962
J. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4961–4966
selectivity was optimized for MMP-13 over the closely
related MMP-2, we were likely to achieve selectivity
over MMP-3, -7, and -8 as well.11
ed benzofuran 2-carboxamide P10 moiety, have been
found to be potent and highly selective MMP-13
inhibitors.12
In fact, compound 1a (R1 = R3 = H, R2 = OCH2(CH3)-
CO2H) had been shown to provide 100-fold selectivity
for MMP-13 over MMP-2.10 A smaller methoxy substi-
tuent at the 4-position of the benzofuran of compound
1b (R1 = R3 = H, R2 = OCH3) still yields a potent
MMP-13 inhibitor, but it is unfortunately only 7-fold
selective, since the methoxy group does not probe deeply
enough into the S10 pocket of MMP-2 (Table 1). Simi-
larly, compound 2, the 5-bromobenzofuran derivative,
is non-selective, though extremely potent against
MMP-13. This is in accord with the predicted structure
of 2 bound to MMP-2 and -13, as the 5-position is not
directed at the S10 loop region of MMP-2 which differs
from that of MMP-13.
The first disubstituted analog prepared was benzofuran
carboxamide 3, a hybrid of compounds 1b and 2, substi-
tuted at both the 4- and 5-positions. While this deriva-
tive is extremely potent against MMP-13, it still
displays only 18-fold selectivity over MMP-2, not a sub-
stantial improvement. However, we were delighted to
find that when a methyl substituent is appended to the
3-position of 4,5-disubstituted benzofuran 3 to provide
the 3,4,5-trisubstituted benzofuran amide 4, selectivity
improves quite drastically. Thus, compound 4 retains
potency against MMP-13 (IC50 = 2.3 nM), but is also
now more than 700-fold selective over MMP-2. Further-
more, compound 4 is not only very selective over MMP-
2, but also has significantly improved selectivity against
MMP-3 (IC50 = 144 nM), MMP-7 (IC50 = 866 nM),
MMP-8 (IC50 = 73 nM), and maintains the selectivity
over MMP-1 (IC50 = 30 lM), MMP-9 (66% inhibition
at 25 lM), MMP-14 (IC50 = 15 lM), Aggrecanase 1
(IC50 = 5.6 lM), and TACE (IC50 = 34 lM) in accord
with our initial assumption. To assess the origin of this
excellent selectivity, three additional analogs bearing the
3-methyl substituent, 5, 6, and 7, were prepared. Elimi-
nation of the 5-bromo group from analog 4 gave
3-methyl-4-methoxy benzofuran 5 and resulted in a
slightly diminished MMP-13 potency and a concomitant
diminution of selectivity to 110-fold. Deletion of the
4-methoxy group from 4 provided analog 6, essentially
equipotent to 4 against MMP-13, but with a devastating
loss of selectivity to only 27-fold selective over MMP-2.
Finally, the 4,5-unsubstituted 3-methyl benzofuran 7
was 44-fold selective. Therefore, the exceptional selectiv-
ity of compound 4 for MMP-13 over MMP-2 clearly re-
sults from a synergistic effect of all three 3-, 4-, and 5-
substituents on the P10 benzofuran.
We now report on our efforts to enhance the selectivity
of these inhibitors for MMP-13 over MMP-2 by extend-
ing the SAR of this scaffold to compounds bearing mul-
tiple substituents on the benzofuran P10 ring system.
The resulting novel biphenyl sulfonamide carboxylic
acids of general structure 1, bearing a 3,4,5-tri-substitut-
Table 1. Identification of groups that are responsible for the selectivity
Compound No. Ar
IC50 (nM)a
MMP-2 MMP-13 MMP-2/
MMP-13
MeO
1b
2
16
2.3
7
1
O
The potency and selectivity of compound 4 can be ex-
plained on the basis of modeling studies based on
X-ray crystallographic data (Fig. 2). Computational
studies of the 3D conformations of 4 suggest that the
3-methyl group causes the conjugated amide-benzofuran
system to be displaced from planarity by about 20 de-
grees, which helps direct the 4-methoxy substituent
directly toward THR229 of the MMP-2 S10 pocket.
The bromine atom at position 5, with its large van der
Waals radius, additionally helps constrain the mobility
of the methoxy group such that, if the molecule were
docked like the unsubstituted benzofuran analog, 1,
the methyl group of the methoxy moiety would lie with-
Br
0.91 0.61
O
MeO
Br
3
7.1
0.4
2.3
9.5
3.0
5.9
18
O
MeO
Br
4
1700
740
110
27
O
MeO
5
1050
81
˚
in 1.8 A of the THR229 Cb atom. No such steric clash
exists for the benzofuran substituents with the S10 pock-
et of MMP-13.
O
Br
6
O
The effect of the configuration of the amino acid portion
of the biphenyl sulfonamide scaffold on potency and
selectivity was investigated. A comparison of the (S)-
and (R)- isomers of three benzofuran P10 analogs is
shown in Table 2. The pair of enantiomers, 1 and 8,
bearing the unsubstituted benzofuran P10 group has
virtually identical potency against both MMP-13 and
7
259
44
O
a The assays used to obtain the data for this table were performed as
detailed in Ref. 12.

J. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4961–4966
Table 3. SAR of 3-substituted benzofuran 2-carboxamide P10
4963
T229
Compound R1
No.
IC50 (nm)
MMP-2 MMP-13 MMP-2/MMP-13
G248
S250
1
7
H
CH3
5
259
2.4
5.9
2
44
32
6
11
12
CH2CH3 1770
Ph 1200
55
220
was increased further, selectivity does not increase pro-
portionately. In addition, the potency of the inhibitors
decreased rapidly as the size of the 3-substituent was in-
creased from methyl to ethyl to phenyl. Compound 11,
with an IC50 of 55 nM, is almost 10-fold less potent than
methyl derivative 7, and the phenyl analog, 12, is more
than 30-fold less potent than 7. Overall, the methyl
group appears to offer the best combination of potency
and high selectivity.
Figure 2. A close-up and schematic view of the predicted binding
mode of compound 4 to MMP-13, overlaid with the catalytic domain
of MMP-2. The white tube represents MMP-13, while the cyan tube
represents MMP-2. The blue coloring in the MMP-13 tube highlights
the positions of amino acid differences between the two proteins.
Table 2. Comparison of potency and selectivity of (R)- and (S)-
isomers
With the 3-position of the benzofuran 2-carboxamide
fixed, the SAR of a variety of 3,4,5-trisubstituted ben-
zofuran 2-carboxamides was examined. As shown in
Table 4, all inhibitors, 13–18, bearing a 4-methoxy
group on the benzofuran are potent against MMP-13.
Selectivity does not vary significantly with the size of
the halogen 5-substituent of compounds 4, 13, and
14, all three analogs providing over 650-fold selectivity.
The lowest levels of selectivity in the 4-methoxy series
are seen with the 5-hydroxymethyl moiety, 15, and
the small 5-cyano group, 17, although both of them
are still well over 100-fold selective. A significant in-
crease in selectivity, with no loss in MMP-13 potency,
is also noted in going from the 5-methyl analog 16 to
5-ethyl derivative 18.
Ar
Compound
No.
IC50 (nm)
MMP-2 MMP-13 MMP-2/
MMP-13
*
1
8
(S)-
(R)-
5
4.6
2.4
2.6
2
2
O
7
9
(S)-
(R)-
259
164
5.9
44
10
17
O
4
10
(S)- 1,700
(R)- 688
2.3
3.4
739
202
MeO
Br
Compound 19 has the lowest selectivity (20-fold)
among the 3,4,5-trisubstituted analogs. We speculate
that an intra-molecular hydrogen bond between the
4-hydroxy and 5-acyl group contributes to reduced
selectivity, although we do not have any direct struc-
tural information. In analog 20, where such an orienta-
tional restriction of the hydroxy is absent, selectivity is
even greater (250-fold). Larger 4-substituents are also
tolerated in the 3,4,5-trisubstituted analogs. Thus, the
isopropyl ethers 22 and 23 maintain reasonable poten-
cy and selectivity for MMP-13 over MMP-2. The 4-
benzyloxy derivative, 21, is only moderately potent
against MMP-13, which results in diminished selectivi-
ty over MMP-2.
O
MMP-2. In contrast, for the pair of enantiomers with
the 3-methylbenzofuran P10 terminus, 7 and 9, the (S)-
enantiomer is more potent against MMP-13 and more
selective over MMP-2 than the corresponding (R)-
isomer. A similar SAR exists for (S)-enantiomer 4 and
its epimer, 10. In this case although the MMP-13 activ-
ity is similar for both enantiomers, the (S)-analog is
more than 2-fold less potent against MMP-2.
The optimization of the benzofuran 3-substituent is
shown in Table 3. The potency and selectivity of analogs
bearing groups at the 3-position, ranging in size from a
simple hydrogen atom to a phenyl group, were exam-
ined. Compound 1, the 3-hydrogen derivative, shows
equal activity against MMP-2 and MMP-13. Com-
pound 7, with a methyl substituent, is a 5.9 nM inhibitor
of MMP-13 with 44-fold selectivity for MMP-13 over
MMP-2. However, when the size of the 3-substituent
The synthesis13 of the biphenyl sulfonamide carboxylic
acid is shown in Scheme 1. The preparation of nitro-bi-
phenyl sulfonamide 24 has been reported.14 Reduction
of the nitro group afforded aniline 25 in very good yield.
After coupling of aniline with the benzofuran carboxylic
acid, ester hydrolysis gave the desired products (2–23).
In some cases, the methyl ester of the amino acid was

4964
J. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4961–4966
Table 4. Selectivity of 3,4,5-trisubstituted benzofuran derivativesa
Comp. R2
No.
R3
IC50 (nm), or % inhibition at 25 lM
MMP-1 MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-14 Agg1
TACE MMP-13 MMP-2/MMP-13
4
13
14
15
16
17
18
19
20
21
22
23
OMe
Br
30,000 1,700
60,000 1,370
34,000 1,490
144
1,060
—
866
3,010
—
73
404
—
66%
51%
—
15,000
30,000
12,400
—
5,600 34,000 2.3
740
650
785
180
330
175
660
20
OMe
OMe
OMe
OMe
OMe
OMe
OH
I
Cl
15,000 38%
2.1
1.9
7.8
4.9
3
—
—
—
—
CH2OH
Me
CN
Et
—
1,410
37,100 1,610
522
28,000 2,500
63
23,400 1,760
—
442
—
—
534
—
—
—
52
76%
—
15,000
—
8,600 39%
—
>15,000 43%
—
—
—
561
—
1,260
—
101
—
64%
—
30,000
—
3.8
3.2
7.1
COMe
Et
—
—
—
4,400 42%
—
OH
OCH2Ph Et
492
—
—
458
—
—
94
55%
—
15,800
—
—
250
65
—
—
4,340
7,000
—
—
—
—
67
O(i-Pr)
O(i-Pr)
Et
Cl
—
51%
—
27
11
260
275
37,100 3,010
1,090
1,640
110
50,000
14,300 98%
a Lines indicate that biological activity data for that MMP are not available.
O
OO S
O
OO S
The second approach to the substituted benzofuran
derivatives is shown in Scheme 3. The synthesis of
selected 3,4,5-trisubstituted benzofurans through func-
tionalization (34–39c, 41) and derivatization (42–44) is
presented. Hydroxybenzofuran 30 can be converted to
34 through methylation with methyl iodide in the pres-
ence of potassium carbonate in a polar aprotic solvent,
such as DMF or THF. The reaction of 30 with magne-
sium methoxide, followed by paraformaldehyde, pro-
duces the ortho-formyl phenol, which can be reduced
to the 5-methyl benzofuran or 5-hydroxymethyl benzo-
furan. Subsequent methylations of these benzofuran af-
ford 35 and 36. Phenol 30 and its O-alkylated derivative
34 undergo ortho-acylation with acetyl chloride and
titanium tetrachloride to give acetophenones 38. Com-
pounds of structure 30 are readily halogenated with
N-halogen succinimides to provide 5-halogenated phe-
nol, which, in turn, may be alkylated to give ethers 37
and39. Compound 40 was obtained in the same manner
starting from 33. Palladium catalyzed reaction of 39c
with zinc cyanide, followed by hydrolysis, gives nitrile
41. O-Alkylation of 4-hydroxy-5-ethylbenzofuran 31
NO2
a
NH2
NH
NH
ButO
ButO
25
24
R2
R1
R3
R2
R1
O
O
R3
HOOC
OO S
NH
O
O
NH
ButO
b
R2
R1
O
O
R3
c
OO S
NH
NH
O
HO
2 - 23
Scheme 1. Reagents and conditions: Preparation of benzofuran
biphenyl sulfonamide carboxylates. (a) H2, Pd/C, 50 psi, rt, 5 h,
(90%); (b) BOP, DIEA, DMF, rt, overnight, (40–80%); (c) TFA/
CH2Cl2 (1:1), rt, 3 h, (70–100%).
used and a basic (LiOH/MeOH/H2O) hydrolysis was
carried out.
Most of the substituted benzofuran carboxylic acids we
required were not commercially available and were syn-
thesized in one of the two approaches, as shown in
Schemes 2 and 3. The first approach was to construct
the benzofuran ring with desired substitution (Scheme
2). Salicylaldehydes and ketones A, bearing a variety
of substituents R1, R2, and R3, are alkylated with a-
bromoacetic acid esters to give B, which is next cyclized
in the presence of an alkoxide base in alcohol or potas-
sium carbonate in DMF to afford the substituted
benzofurans C. Esters C are hydrolyzed with aqueous
hydroxide or TFA (for R = t-butyl) to give the carbox-
ylic acids 26–33, which, in turn, can be coupled with ani-
line 25 to make the desired final product. Some of these
acids in Schemes 2 and 3 or their esters have been
reported in the literature including 26,15 27,16 28,17
30,18 32,19 33,20 and 34.21
Scheme 2. Reagents and conditions: Constructing the benzofuran ring
with desired substitution. (a) BrCH2CO2R (R=Me, Et or But), K2CO3,
rt, (70–90%); (b) MeONa, MeOH, 60 °C (40–90%); (c) NaOEt, EtOH,
70 °C, (70–90%); (d) K2CO3, 130 °C, 1 h (60–90%); (e) LiOH, MeOH,
THF, rt. (70–90%); (f) NaOH, H2O, EtOH, (80–90%); (g) TFA/
CH2Cl2(1:1), rt, 4 h, (70–90%).

J. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4961–4966
4965
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O
R1
O
O
R1
O
OH
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Goldberg, R. L.; MacPherson, L. J.; Blancuzzi, V.;
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HO2C
HO2C
HO2C
O
O
35(R1=Me)
34(R1=Me)
36(R1=Me)
b,c
d,e,b,c
d,e,b,c
O
RO
O
HO
R1
O
R1
HO2C
R1
X
a,f,c
g,c
HO2C
ButO2C
O
O
30(R1=Me)
33(R1=H)
37(R1=Me, X=Cl)
38a(R1=Me, R=H)
38b(R1=R=Me)
a,b,h,c
a,b,c
R1
O
R1
O
39a(R1=Me, X=Cl)
39b(R1=Me, X=Br)
39c(R1=Me, X=I)
40 (R1=H, X=Br)
CN
X
HO2C
HO2C
O
41(R1=Me)
O
7. Noe, K. C.; Snow, S. L.; Wolf-Gouveia, L. A.; Mitchell, P.
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HO
O
Ph
O
f,j
i,j
HO2C
HO2C
O
EtO2C
O
O
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42
43
31
b,j
O
HO2C
O
44
Scheme 3. Reagents and conditions: Functionalization and derivatiza-
tion of the benzofuran ring. (a) NXS(NCS for 39a, NBS for 39b and 40,
NIS for 39c), CCl4, 0 °C, 6 h, (50–85%); (b) MeI, K2CO3, DMF, rt,
overnight, (80–100%); (c) TFA/CH2Cl2(1:1), rt, 4 h, (70–90%); (d) (i)
(MgOMe)2/MeOH, toluene, reflux, 1 h. (ii) (CH2O)n, reflux, 30 min,
(50%); (e) NaBH3CN, THF, 60 °C, (30–40%); (f) i-PrBr, K2CO3, DMF,
rt, overnight, (80–100%); (g) AcCl, TiCl4, PhCl, 95 °C, pressure tube,
(40–60%); (h) Zn(CN)2, Pd(PPh3)4, DMF, 85 °C, 2 h, (70%); (i) BnBr,
K2CO3, DMF, rt, overnight, (80%); (j) NaOH, H2O, EtOH, (80–90%).
gives ethers, which are next hydrolyzed in alkoxide base
in alcohol to afford 42, 43, and 44.
10. (a) Wu, J.; Hotchandani, R.; Hu, F.; Levin, J. I.; Li, J.; Li,
W.; Lovering, F.; Morris, E.; Rush, T.; Wang, Q.; Xu, Z.;
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Selective MMP-13 Inhibitors’’ at the meeting of ‘‘Inhibi-
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2005, 87, 393, A manuscript describing the modeling
analyses of MMP S10 pockets is in preparation.
12. (a) The inhibitory ability of small molecules was tested in a
continuous fluorescent assay designed for each enzyme in
which the substrate is a synthetic peptide containing a
fluorescent group (7-methoxycoumarin or 2-amin-
obenzoyl) that is quenched by energy transfer to 2,4-
dinitrophenyl. Enzymes were either prepared at Wyeth
Research (MMP-1, -12, -13, Agg-1, TACE) or purchased
from Calbiochem (San Diego, CA) (MMP-3, -7, -9), R&D
Systems (Minneapolis, MN) (MMP-2), Chemicon Inter-
national (Temecula, CA) (MMP-14), or Biomol (Plym-
outh Meeting, PA) (MMP-8). MMP-2 and MMP-14 were
In summary, we have described a promising series of
biphenyl sulfonamide carboxylic acids that are potent
inhibitors of MMP-13 that spare MMP-1, MMP-2,
MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Agg1,
and TACE. By varying the substituents on the benzofu-
ran portion of the molecules, we were able to modulate
the potency and selectivity of this series of inhibitors.
Further development and the in vivo efficacy of this
series of compounds will be reported in due course.
Acknowledgments
We thank Dr. Nelson Huang, Dr. Yin Ge, and Dr. Wal-
ter Massefski for LC-MS, HRMS, and NMR measure-
ments; Ms. Elizabeth Collins for her contribution to the
selectivity assays and Dr. Kathy Lee for editing the
manuscript.
References and notes
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13. All new compounds gave satisfactory 1H NMR, MS in
accord with their assigned structure.
MMP-1, -2, -7, -9, -13, -14, Agg-1, and TACE have been
previously described12b and identical assay conditions
were used for MMP-3 and -12, except for MMP-3 which
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used
the
substrate
Mca-PKPLAL-Dpa-AR-NH2
(Bachem, King of Prussia, PA). Measurements were
performed in fluorimeter plate readers at the excitation
and emission wavelengths of the fluorophore. Note that
while IC50 values were reported, the assays were estab-
lished in such a way as to keep the IC50 and Ki within 2-
fold of each other by manipulating the relationship
between a given MMP substrate concentration and its
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